It has been reported that glycogen synthase kinase-3 beta (GSK-3β), a protein kinase, is involved in the causes of various diseases as noted in the following.
Type-II diabetes is a disease in which the insulin reactivity of pancreatic β cells becomes low and glucose in blood increases. As a result, complications such as diabetic nephropathy, retinosis, heart disease and the like are induced. GSK-3β acts for inhibiting glycogen accumulation in peripheral tissues, lowering insulin response and increasing glucose in blood by phosphorylating glycogen synthase. Lithium having a GSK-3β-inhibitory activity actually lowers glucose in blood by a GSK-3β-inhibitory activity (Proc. Nat. Acad. Sci., 93, 8455 (1996)). Therefore, medicaments having a GSK-3β-inhibitory activity are considered to be a pharmaceutical agent effective for the improvement of Type II diabetes and complications thereof.
The developmental mechanism of Alzheimer's dementia has not yet been elucidated. However, it is considered that amyloid aggregation and neurofibril changes are closely related to the cause of the development. GSK-3β is involved in both the amyloid aggregation and the neurofibril changes as follows. (1) It binds with variant presenilin and increase production of insoluble amyloid (Proc. Nat. Acad. Sci., 95, 9637 (1998)). (2) It causes phosphorylation of the Tau protein, which causes neurofibril changes, and weakens the backbones of neurons to induce neuronal death (Neurosci. Lett., 128, 195 (1991)). In addition to the above, (3) the direct involvement of GSK-3β in nuronal death through inactivation of pyruvate dehydrogenase by phosphorylation to decrease the production amount of acetylcholine necessary for maintaining cell activity (Proc. Nat. Acad. Sci., 93, 2719 (1996)) has been reported.
In addition, the effectiveness for AIDS encephalopathia as a neurodegenerative disease other than Alzheimer's dementia has been suggested. Tat, which is a protein produced by HIV virus that causes AIDS, enhances GSK-3β activity in neurons to induce neuronal death (J. Neurochem., 73, 578 (1999)). From the above, GSK-3β inhibitors are considered to be medicaments effective for improving neurodegenerative diseases including Alzheimer's dementia.
Lithium and valproic acid, which have anti-manic-depressive activity, have a GSK-3β inhibitory activity (J. Neurochem., 72, 1327 (1999)). The relationship between anti-manic-depressive activity and GSK-3β inhibitory activity is unclear, but a suppressive activity on glutamic acid toxicity is considered to be partly responsible for maintaining neuronal activity (Proc. Nat. Acad. Sci., 95, 2642 (1998)). Based on the foregoing, GSK-3β inhibitors are considered to be medicaments effective for improving manic-depressive psychosis.
NF-AT, a transcription factor, is dephosphorylated by calcineurin to increase immunological responses (Science, 275, 1930 (1997)). GSK-3β acts for suppressing immunological function by conversely phosphorylating NF-AT. Therefore, GSK-3β inhibitors are considered to be medicaments effective for immunopotentiation.
Incidentally, JP-A-3-272189 (invention drawn to an improved synthesis method of mevalolacton intermediates), JP-A-2-275878 (therapeutic agents for hyperlipoproteinemia and atherosclerosis) and JP-A-1-272584 (therapeutic agents for hyperlipoproteinemia) disclose pyrazolo[3,4-b]pyridine compounds wherein the 6-position is either methyl, isopropyl or cyclopropyl. These publications do not disclose or suggest any action of these compounds on GSK-3β or the central nervous system.
The specifications of JP-A-59-65089, JP-A-59-118786, JP-A-60-56979, JP-A-60-197685 and the like disclose 6-methyl-4-substituted phenyl-4,7-dihydropyrazolo[3,4-b]pyridine-5-carboxylate compounds used for the treatment of cardiovascular diseases, and they are produced by similar methods. The present inventors reproduced the following reaction A according to the method described in JP-A-59-65089, but failed to obtain the compound of Example 14 (formula (IV) in the following) described therein. They confirmed that only the pyrazolo[1,5-a]pyrimidine derivative represented by the formula (V) could be produced. They measured IR, NMR and the melting point of the compound of the formula (V) and found them to be identical with IR, NMR and the melting point described in the specification of this publication. It is therefore concluded that an erroneous structural formula has been disclosed in these publications. In other words, 6-methyl-4-substituted phenyl-4,7-dihydropyrazolo[3,4-b]pyridine-5-carboxylate cannot be synthesized according to the methods described in these publications. 
The compound of the above formula (IV) can be synthesized according to the method described in J. Chem. Soc., Perkin Trans. 1, 947 (1996), and this publication discloses methyl 4-(2-chlorophenyl)-6-methyl-4,7-dihydro-1H-pyrazolo[3,4-b]pyridine-5-carboxylate and the like.